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Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(11)C]methyl-L-tryptophan (11C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized 11C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2). In all, 46 healthy controls had PET 11C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of 11C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Suicide is the most serious consequence of major depressive disorder (MDD). Although the anterior cingulate cortex (ACC; Brodmann area [BA] 24) has been increasingly investigated for its role in the etiology of MDD, there is surprisingly very little information about the possible implication of this brain region in suicide. We hypothesized that changes in BA24 cell densities occur in depressed individuals who commit suicide, possibly reflecting an altered state of cortical plasticity that is thought to occur in depression. METHODS: We investigated cell densities and sizes in BA24 among suicide completers and matched sudden-death controls. We examined a 1-cm(3) tissue block from BA24a of the supracallosal ACC in 26 human postmortem brain specimens (13 depressed individuals who committed suicide and 13 controls). We assessed neuronal and glial cell densities as well as neuronal soma sizes in the upper and lower cortical layers using optical fractionator and nucleator 3-dimensional stereological probes. RESULTS: Glial densities, neuronal densities and soma sizes measured in BA24a did not differ significantly between controls and suicide completers. Secondary analyses showed a significant and robust increase in glial cell densities in BA24a of alcohol-dependent depressed suicide completers compared with depressed suicide completers who were not alcohol-dependent (38%) and, to a lesser extent, controls (30%). LIMITATIONS: Our study, conducted with tissue samples from men only, made use of a nonspecific stain that does not distinguish between neuronal or glial cell subtypes. Furthermore, the quantitative analysis concerned upper and lower cortical contours rather than individual cortical layers. CONCLUSION: Our results indicate that in BA24, glial density, neuronal density and soma size are not affected in MDD and suicide. They also suggest that alcohol dependence has an important influence on glial densities in this key limbic structure. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD. METHODS: Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein. RESULTS: BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment. CONCLUSION: Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested. [ABSTRACT FROM AUTHOR]

The polyamine pathway has an essential role in many cellular functions and has been implicated in several pathological conditions. Accumulating evidence suggests that the polyamine system also plays a role in the etiology and pathology of mental disorders. Alterations in the expression and activity of polyamine metabolic enzymes, as well as changes in the levels of the individual polyamines, have been observed in multiple conditions, including schizophrenia, mood disorders, anxiety and suicidal behaviour. Additionally, these components have been found to be altered by various psychiatric treatments. Further, the polyamines and their precursors have demonstrated both antidepressant and anxiolytic effects. Overall, findings to date suggest that the polyamine pathway represents an important frontier for the development of neuropharmacological treatments. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Little is known about differential suicide profiles across the life trajectory. This study introduces the life-course method in suicide research with the aim of refining the longitudinal and cumulative assessment of psychosocial factors by quantifying accumulation of burden over time in order to delineate distinctive pathways of completed suicide.MethodThe psychological autopsy method was used to obtain third-party information on consecutive suicides. Life-history calendar analysis served to arrive at an adversity score per 5-year segment that was then cluster-analysed and correlated to define victim profiles. RESULTS: Two distinct life trajectories emerged: (1) individuals who experienced childhood traumas, developmental adversity and little protection were more likely to present concurrent psychiatric and Axis II disorders; and (2) individuals who experienced less adversity but seemed more reactive to later major difficulties. CONCLUSIONS: The life calendar approach presented here in suicide research adds to the identification of life events, distal and recent, previously associated with suicide. It also quantifies the burden of adversity over the life course, defining two distinct profiles that could benefit from distinct targeted preventive intervention. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Suicidal behaviors in young individuals represent an important public health problem. Understanding their natural history and relationships would therefore be of clinical and research value. In this study, we examined the natural histories of several suicidal behaviors and investigated two conceptual models of suicidality (dimensional and categorical) in the context of adolescent and adult-onset suicide attempts.MethodParticipants were members of a prospectively studied, representative, population-based school cohort followed since age 6 (n=3017) through mid-adolescence (n=1715) to their early twenties (n=1684). Outcome measures included suicidal ideation, attempts and completions. RESULTS: Approximately one in 500 individuals died by suicide. About 33% had suicidal ideas and 9.3% made at least one suicide attempt. Over half (4.9%) of the self-reported attempters made their first attempt before age 18. With the exception of current suicidal ideas, non-fatal suicidal behaviors were more prevalent in females. In general, parental and cross-sectional self-reports underestimated suicidality rates. Aikaike (AIC) and Bayesian (BIC) information criteria suggested the ordinal model, and dimensional conceptualization of suicide attempts of different onset age, to be more optimal than its multinomial/categorical counterpart (ordinal: AIC 567.55, BIC 635.67; multinomial: AIC 616.59, BIC 723.83). Both models, nevertheless, identified five common factors of relevance to suicidal diathesis: gender, disruptive disorders, childhood anxiousness and abuse, and suicidal thoughts. CONCLUSIONS: Non-fatal suicidal behaviors in adolescents and young adults are more common than suggested by cross-sectional studies and parental reports. The dimensional model may be more useful in explaining the relationship of suicide attempts of different age of onset. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND: Identification of factors that distinguish between ideators who act on their suicidal thoughts from those who do not is an important clinical and research objective.MethodWe examined correlates of suicide attempts in suicidal ideators, members of a French-Canadian, school-based cohort. Suicidal thoughts were evaluated in adolescence and early adulthood in the total sample of suicidal ideators, who were then stratified into subgroups consisting of persistent ideators, male ideators and female ideators. RESULTS: In addition to persistent suicidal ideas [odds ratios (ORs) 2.1-2.8], Axis I psychopathology, female gender and childhood sexual abuse (CSA) were the most consistent correlates of suicide attempts. Externalizing disorders were significant contributors in persistent ideators [drug misuse: OR 2.8, 95% confidence interval (CI) 1.1-6.9] and in male ideators in particular (disruptive disorders: OR 5.9, 95% CI 2.2-16.0). In women, psychiatric co-morbidity also had a significant effect (OR 1.6, 95% CI 1.1-2.1). CSA was of relevance in both women (OR 1.2, 95% CI 1.1-1.4) and persistent ideators (OR 1.3, 95% CI 1.1-1.5). Personality traits showed gender-specific contribution with affective instability (OR 1.1, 95% CI 1.01-1.1) and anxiousness (OR 1.3, 95% CI 1.1-1.7) contributing in men and disruptive aggression (OR 1.1, 95% CI 1.03-1.3) in women. CONCLUSIONS: Correlates of suicide attempts in suicidal ideators vary as a function of the persistence of suicidal ideas and gender. This heterogeneity across subgroups of suicidal ideators may be attributed, at least in part, to differences between the sexes, early environmental adversity, maladaptive personality, and psychiatric symptoms. Further exploration and continued prospective follow-up is necessary to examine these possibilities. [ABSTRACT FROM AUTHOR]

BACKGROUND: Adults in their twenties appear to be at high risk for suicidal behaviors (SBs) and there is substantial evidence suggesting that certain personality traits may increase individual vulnerability to suicide. METHOD: We investigated relationships of personality traits with two SBs in a cohort (n=1140) of 21- to 24-year-old adults, representative of the general population of Quebec. Subjects were assessed using a series of structured diagnostic and personality trait questionnaires. Multivariate logistic regression analyses were employed to identify personality trait correlates of suicide-attempt history and serious suicidal ideation in the context of other known risk factors, such as psychopathology and experiences of childhood sexual and physical abuse. RESULTS: Traits of conduct problems contributed to both suicide attempts [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06] and suicidal ideation (OR 1.04, 95% CI 1.02-1.07), while identity problems (OR 1.10, 95% CI 1.07-1.13) and gender-moderated impulsivity contributed exclusively to suicidal ideation. CONCLUSIONS: Personality traits may make independent contributions to current suicidal ideation and previous suicide attempts in certain subgroups of suicidal individuals. In order to further explore their utility as markers of suicide risk and targets of intervention further investigation in clinical samples and other cultural and age groups is necessary. [ABSTRACT FROM AUTHOR]

Suicide ranks among the main causes of death in most Western countries and is, thus, an important public health problem. Over the last few years, it has been increasingly recognized that people who attempt or commit suicide have a certain individual predisposition, partly resulting from certain personality traits, in particular, impulsive-aggressive behaviors. The evidence suggests that impulsive-aggressive traits are part of a developmental cascade that increases suicide risk among a subset of suicides. These personality traits may also mediate familial transmission of suicidal behavior, defining a behavioral endophenotype that could be useful in molecular genetic studies of suicide. On the other hand, not all suicides are associated with impulsive-aggressive behaviors. There is a need to better understand the mechanisms mediating suicide among individuals with no history of impulsive-aggressive behaviors. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a major psychiatric condition that commonly requires prophylactic and episodic treatment. There is important variability in the therapeutic response and side-effect profiles to currently available pharmacological agents. Pharmacogenetics have provided new hopes to develop more efficient treatment strategies tailored to the individual patient's needs. This review assesses nonsystematically studies using pharmacogenetic strategies in BD. Most of these studies have focused on patients selected according to lithium response, and more recently, a growing number of studies have been investigating genetic factors in mixed samples of patients classified according to response to antidepressant treatment. Although previous clinical and family studies support the use of pharmacogenetic strategies both to increase phenotype homogeneity as well as to identify genetic factors that may mediate response to treatment, most molecular studies carried out to date are still preliminary and in need of external validation. A major problem has been comparability between studies, in part, because of differences in the criteria used to define response. More attention should be paid to standardize the criteria for drug response definition.The Pharmacogenomics Journal (2004) 4, 161-170. doi:10.1038/sj.tpj.6500245 Published online 13 April 2004 [ABSTRACT FROM AUTHOR]

The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/ deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H[sub w] OR) = 1.17 C1:1.04-1.32, P = 0.009), but not for the 5-HT2A 102 TlC variant (M-H[sub w] OR) = 1.09 CI: 0.93-1.27, P = 0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide. [ABSTRACT FROM AUTHOR]

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR = 1.14, CI: 1.03-1.26, P = 0.015 for the promoter locus (N = 3467) and Mantel-Haenszel Weighted odds ratio OR = 1.18, CI: 1.05-1.32, P = 0.004 for the VNTR locus (N = 3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between... [ABSTRACT FROM AUTHOR]

Evaluates the mapping susceptibility genes for bipolar disorder (BD) using a pharmacogenetic approach based on excellent response to lithium. Administration of a complete genome scan using markers; Evaluation of response to lithium with an average follow-up of 12 years; Role of the locus on chromosome 15q14 in the etiology of BD.

Investigates the link between tryptophan hydroxylase (TPH) and suicide completion. Association between the gene that codes TPH and suicidal behavior; Genotyping of a sample of suicide completers; Public-health problem of suicidal behavior; Evidence that subjects with suicidal behavior have reduced serotonergic neuro-transmission.

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better longterm outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C→T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional5 and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome. [ABSTRACT FROM AUTHOR]

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a γ-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ± 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (χ² = 8.09; empirical P=0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD=1.45; empirical P=0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is impli- cated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined. [ABSTRACT FROM AUTHOR]

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamineexpanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab lC2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: The objective of this study is to measure the association between protein-energy malnutrition (PEM) in children and their mothers' mental health, in a low income area in the city of Embú, São Paulo, Brazil.Methods: A case-control study was performed. Cases were 60 moderately and severely malnourished children (Gomez criteria) selected from two primary health care units. Controls consisted of 45 eutrophic children attending the same units. The main outcome measure was for the mothers to present a mental health score > 6 according with the 'Adult Psychiatric Morbidity Questionnaire' (QMPA), a psychiatric screening instrument.Results: Of mothers of children with PEM, 63% and 38% of mothers in the control group were QMPA positive: odds ratio (OR) = 2.8 (95% confidence interval [CI]: 1.2-6.9). Of PEM children, 27% had low birthweight (LBW = < 2500 g) and 6% of the control group had LBW. Interactions were found between: mothers' mental health and number of children (with > or = 4 children: OR = 20.0 [95% CI: 2.1-274.2], with < or = 3 children: OR = 1.6 [95% CI: 0.6-4.5), as well as mothers' mental health and maternal age (in women > 30: OR = 12.5 [95% CI: 2.0-93.4], in women < or = 30: OR = 1.5 [95% CI: 0.5-4.4].Conclusions: Mothers of children with PEM showed a higher rate of mental disturbances than mothers of eutrophic children. Unlike LBW, maternal age and number of children interact with mothers' mental health, increasing the association. Management of poor mental health may lead to mothers being better caretakers of their children and this may have a positive impact on PEM. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in relation to histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers.

Objective: This study compared suicidality in families of adult male suicide completers and community comparison subjects. Method: Two hundred forty-seven relatives of 25 male suicide completers and 171 relatives of 25 matched comparison subjects were assessed for recurrent risk of suicidal and related behaviors. Analyses were performed on a subgroup of relatives of suicide completers with cluster B personality disorders. Results: Relatives of suicide completers were over 10 times more likely than relatives of comparison subjects to attempt or complete suicide after the authors controlled for psychopathology. Relatives of suicide completers were not more likely to exhibit suicidal ideation but had more severe suicidal ideation than relatives of comparison subjects. These findings were stronger for the suicide completers diagnosed with cluster B personality disorders. Conclusions: Suicide has a familial component independent of psychopathology that may be mediated by a combination of factors, including more severe suicidal ideation and aggressive behavior. [ABSTRACT FROM AUTHOR]